Immunity. ES/RP 531 Fundamentals of Environmental Toxicology. Lecture 14 Immunotoxicity. Instructor: Allan Felsot

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1 Instructor: Allan Felsot Fall 2005 ES/RP 531 Fundamentals of Environmental Toxicology Lecture 14 Immunotoxicity in Humans Hematopoiesis (generation of blood cells) Differentiation of Blood Cells Stem Cells White Blood Cells (leukocytes) Erythrocytes (O 2 carriers) Megakaryocytes (blood clotting) Immune System Cells nology/tutorials/immunology/02t.html Pluripotent Stem Cell Differentiation to Leukocytes in Mammals Immunity Pluripotent Stem Cell Common Progenitor Common Myeloid Progenitor Immature Lymphocyte Granulocyte Series Monocyte T-lymphocyte B-lymphocyte Neutrophil Basophil Eosinophil Mast Cell Macrophage Weeks et al Non-specific, Innate Immunity First line of defense More accurately described as broadly specific No memory i.e, after infection, cells do not recognize specifically the pathogen or toxin Specific, Adaptive (or Acquired) Immunity Second line of defense Activated by and directed against specific antigens : a protein or other substance that elicits immune system activation : anything that can be bound by an antibody Has memory: increases with strength after each encounter with pathogen or toxin 1

2 Innate Immunity Physical Barriers Skin, mucous membranes Physiological factors ph, temperature, oxygen tension limit pathogen growth Protein secretions into external body fluids Lysozyme enzyme (saliva, tears) Complement, interferons, C-reactive proteins Phagocytic cells Including macrophages & polymorphonuclear leukocytes Recognize foreign cells by broadly specific receptors (usually for carbohydrate structures on cell) Nonspecific Innate Immunity: Phagocytosis of Foreign Cells Epidermal surface Wound introduces bacteria Inflammation Bacteria Granulocyte Macrophages Blood vessel walls Red Blood Cells Acute Inflammation Acute inflammatory response is a key characteristic of the innate immune system Many infections, especially where small wounds are entry routes, are eliminated by the combination of complement and recruitment of phagocytes Functionality Reduces spread of damaging agents to nearby tissues Increases disposals of cell debris and pthagens Facilitates repair processes Caused by release of histamine and prostaglandins by certain leukocytes Adaptive Immunity Immune response activated by and directed against specific antigens I.e., response mechanism is adapted to idiosyncrasies of the foreign cell or toxin Characterized by memory Once challenged with an antigen, immunity will persist to this specific antigen Causes a decrease in lag time and an increase in response level to repeated infections Two Types of Mechanisms (both involving differentiated lymphocyte cells) Humoral Immunity (involves B cells) Cellular Immunity (involves T cells) Memory in Adaptive Immunity: Second exposure to antigen produces a faster and higher level of response Antibody Titer A: Injection on Days 1 & 28 Days A: Injection on Day 28 Pluripotent Stem Cell Common Progenitor Thymus T-Lymphocytes T Proliferation of T-Regulatory Cells T-Effector Cells Circulation Lymph Nodules Lymph Nodes Spleen Bone Marrow Bursa Equivalent Tissue B-Lymphocytes Secondary Proliferation Plasma Cell Based on Weeks et al B Primary Differentiation Antibody Distal Intestine 2

3 osed Circulatory System of Mammals Capillary walls are permeable, so under high pressure there is some leakage of fluid across the walls into the spaces between cells Lymphatic system recovers the fluid lost to tissues Lymph returns to the blood circulation through the portal venous system % of total volume Pluripotent Stem Cell Common Progenitor Thymus T-Lymphocytes T Proliferation of T-Regulatory Cells T-Effector Cells Circulation Lymph Nodules Lymph Nodes Spleen Bone Marrow Bursa Equivalent Tissue B-Lymphocytes Secondary Proliferation Plasma Cell Based on Weeks et al B Primary Differentiation Antibody Distal Intestine Binding Site Basic Structure of Antibody Variable Constant Binding Site Light Chain Heavy Chain Binding of to Antibody via Epitopes at Variable Region Site Specific Antibody T-Helper Cell Scanning electron micrograph showing interaction between a macrophage (gray structure) and lymphocyte (red structure) during the attack on a Streptococcus bacterium B Cells Antibody Secretion onal Selection Plasma cell Memory cells 3

4 apoptosis Cytotoxic T Cells (called CD8 cells) interact with helpter T cells & recognize specific antigen fragments on surface of infected cells. Infected cells are killed in process called apoptosis Lymphokines T DTH Lymphotoxin Macrophage T H T C T S Immunoglobulins Weeks et al B-cell Plasma Cell Antibodies Specific (Adaptive) Immunity (Cell & Humoral-Mediated) Summary Diagram of Immune Cell Differentiation & Proliferation Nonspecific Immunity (Phagocytosis & Inflammation) 4

5 Ah Receptor Mediated Immunotoxicity Certain polyhalogenated hydrocarbons, dibenzodioxins, and dibenzofurans cause immunotoxicity characterized by a wasting syndrome, atrophy of the thymus, & alterations in T- cell mediated immune functions Especially includes certain PCB congeners and chlorinated dibenzodioxin & dibenzofuran congers The detailed mechanism of how these compounds cause immunotoxicity is unknown but all of them react with a receptor called AhR that causes the transcription of arylhydrocarbon hydroxylase, a P-450 mediated microsomal enzyme (i.e., P-4501A1) The most potent of these immunotoxins is TCDD O (2,3,7,8-tetrachlorodibenzo-p-dioxin) Ah Receptor Mediated Toxicities O Case Study: Marine Mammals Exposed to Polyhalogenated Aromatic Hydrocarbons Contaminant levels observed in seals after fasting for 15 days following consumption of Baltic (contaminated) fish and Atlantic (comparatively uncontaminated) fish (de Swart et al. 1996) Problem: Marine mammals seem to be exhibiting high incidence of disease In some cases beachings seem to have no natural cause de Swart et al. (1996) fed contaminated herring to one group of seals and comparatively uncontaminated herring to another group of seals The contaminants included PCBs, DDT, and dioxin (expressed as toxic equivalents based on TCDD, tetrachlorodibenzo-p-dioxin) Measured residues in fat and blood and immunological activity before & after fasting DDT TCDD PCBs Sum TEQs Baltic fish Atlantic fish Immunological Parameters--Contaminated Herring Group Relative to Uncontaminated Herring Group de Swart et al. 1996, EHP Supplements Immunological Parameter NK (natural killer) cells T lymphocytes B lymphocytes Hematology: Lymphocyte Counts in Peripheral Blood Hematology: Neutrophhil Counts in Peripheral Blood Effect Down Down No Difference No Difference Up Conclusions from Herring Feeding Study Immunological parameters representing specific immunity (lymphocytes) were down regulated in association with higher levels of polyhalogenated aromatic hydrocarbon compounds in fat and blood Neutrophils in blood (represented nonspecific immune response) were upregulated Natural populations exposed to similar levels of contaminants may experience effects on immune system de Swart et al

6 de Swart et al Conclusion from Herring Feeding Study--Fasting Effects Do PCBs Cause Immunotoxicity in Fish? Fasting was associated with a 2-fold increase in blood levels of polyhalogenated organochlorines, but no effect on blood levels of Ah receptor-binding compounds Fasting alone, regardless of diet caused a 35% drop in circulating lymphocytes and a slight increase in NK-cell activity However other lymphoproliferative response remained the same in the contaminated herring group. Short-term fasting did not present an additional immunotoxic threat PCBs have been implicated as immunotoxins based on rat studies Powell et al fed different levels of PCBs to fish PCBs were formulated as Aroclor 1254 Challenged fish with pathogen Some fish vaccinated, others not vaccinated Powell et al Powell et al % Cumulative Mortality Controls, Challenged Unvaccinated % Cumulative Mortality Controls, Unvaccinated No Effects of PCB Feeding on Pathogen-Challenged Salmon No Effects of PCB Feeding on Non Pathogen-Challenged Salmon 6